This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Depression disorder is a common health problem that affects approximately 20% of the population in the United Sates. With current treatment drugs suffering from major shortcomings that include slow onset of action, poor efficacy, and unwanted side effects profile, the search for new and improved antidepressants is ever increasing. Since most of the available antidepressant drugs are based on the monoamine hypothesis and target this system, a recent interest emerged in better understanding the etiology of depression and unraveling new pathways involved in the pathogenesis of this disorder and thus can serve as potential new therapeutic targets. Among the newly emerging pathways involved in depression is the endocannabinoid system that interacts with the constituents of the cannabis plant. Since anecdotal reports commonly list mood elevation as a component of the experience elicited by cannabis users, the idea of harnessing this effect and using it to treat depression has been lingering around the scientific research arena for a while. Recently, compelling experimental evidence has accumulated that supports the role of the endocannabinoid system in the etiology of depression and reinforce the potential therapeutic value of cannabinoids in depressive disorders. These lines of evidence include: 1) Knockout animal models lacking the cannabinoid CB1 receptors are more susceptible to developing depressive behaviors, 2) Activation of the cannabinoid CB1 receptors either directly by agonists or indirectly through elevation of endogenous cannabinoids elicit antidepressant-like actions in experimental animals, 3) Treatment with cannabinoid receptor agonists enhances hippocampal neurogenesis, an effect recently recognized as essential for antidepressant action. While the psychoactive side effects and abuse potential are considered a major obstacle to the therapeutic utilization of cannabis, preliminary studies in our laboratory have demonstrated that [unreadable]9-THC exerts antidepressant-like actions at doses below those eliciting the psychoactive properties. In addition, other non psychoactive cannabinoids, particularly cannabidiol, displayed antidepressant effect in animal models of behavioral despair. Thus our hypothesis is that some of the cannabinoids isolated from cannabis in fact can exert antidepressant action and that the mechanism of such action involves interaction with the brain endocannabinoid and monoaminergic systems, as well as enhancement of neurogenesis. The specific aims of the project are: 1. To establish the antidepressant-like action of major cannabinoids and separate such action from the psychoactive effects of these cannabinoids. 2. To establish the mechanism of antidepressant action exerted by cannabinoids. 3. To establish the role of cannabinoid CB2 receptors in depression.